Olanzapine toxicity

Olanzapine is a second-generation atypical antipsychotic. Widely used, therefore a fairly common presentation to the emergency department. Olanzapine like queitiapine has a predictable dose-dependent CNS depression.

Toxic Mechanism:

Olanzapine antagonizes the mesolimbic dopamine (D2), serotonin, histamine in the muscarinic M1 and peripheral alpha 1 receptor. This causes an anticholinergic effect (muscarinic receptors) in overdose and drowsiness (histamine receptor blockade).

Toxicokinetic: 

• Rapidly absorbed, oral or sublingual
• Large volume of distribution 10-20 L/kg
• Large first pass effect
• Hepatic metabolism to inactive water-soluble metabolites

Resuscitation:

• Reduced GCS: Prompt intubation and ventilation
• Hypotension: Give 10 – 20 ml/kg of IV crystalloid, if response is not adequate start noradrenaline (adrenaline is contraindicated due to paradoxical hypotension from beta 2 mediated vasodilatation). Noradrenaline dose: 0.15mg/kg in 50ml D5W at 1-10ml/hr (0.05 – 0.5 mcg/kg/min)
• Seizures (rare)/agitation: IV benzodiazepines incrementally dosed every 5 minutes to effect.
• Check the patient is not in a dysrhythmia
• Can be managed with benzodiazepines (varying doses in the textbooks, easy method is 0.1mg/kg IV for lorazepam (max 4mg) / midazolam (max 10mg) / diazepam (max 10mg). Or…
• Lorazepam 0.1mg/kg max 4mg
• Diazepam 0.15mg/kg max 10mg
• Midazolam 0.2mg/kg max 10mg

Risk Assessment

• Dose-related risk assessment:

 <40 mg:Effect: Therapeutic sedation and antipsychotic effects (occasionally used for serotonin toxicity).

 40 - 100 mg:Effect: Mild-to-moderate sedation with potential for anticholinergic effects.

 100 - 300 mg:Effect: Sedation with intermittent restlessness.

 >300 mg:Effect: Increasing sedation progressing to coma, requiring intubation.

• Children: the toxic dose is unclear but symptoms are likely to develop when >0.5 mg/kg have been ingested. Delayed extrapyramidal effects can occur in children days later.
• Clinical features should manifest within 2 – 4 hours and may last 48 hours (coma usually lasts 24 – 48 hours)
• Sedation, ataxia, miosis (unlike the mydriasis commonly seen with anticholinergics), fluctuating mental status.
• Reduced GCS, miosis and tachycardia is almost pathognomonic of olanzapine overdose in the western world.
• Tachycardia and orthostatic Hypotension
• Mild to moderate anticholinergic syndrome

Supportive Care

• Controlling the delirium can be difficult, things to consider include
• Titrated doses of benzodiazepines e.g. diazepam 2.5 – 5 mg every 5 minutes IV until gentle sedation is achieved (doses used may necessitate intubation).
• Controversially, physostigmine has been used which has been reportedly reversed agitation and olanzapine comas but has its own side effect profile.
• Physical restraint
• Bladder scan and a catheter for urinary retention (no amount of benzodiazepines will fix this agitation)

Investigations

• Screening: 12 lead ECG, BSL, Paracetamol level
• Specific:
• ECG monitoring, do an ECG at presentation and 6 hours, if this is normal then cardiac monitoring may stop. If intubated, then the patient will need ECG every 4 hours until clinical symptoms or cardiac abnormalities resolve. Non-specific ST – T wave changes occur in 15%, minor QT prolongation but no Torsades de pointes reported

Decontamination:

• Rarely used as the onset of coma and resolution is rapid and good supportive care ensures a good outcome.

Enhanced Elimination

• Not clinical useful

Antidote

• None available

Disposition

• Children who have ingested >0.5 mg/kg should be observed in hospital for 4 hours, if asymptomatic they can be discharged but warned they may develop extrapyramidal movements up to 3 days later.
• Patients should be observed for 4 hours, if asymptomatic with a normal baseline ECG, no hypotension and eating and drinking they can be medically cleared
• Patients with any clinical features should be observed or treated as required until symptoms have resolved. Depending on severity, patients may stay in an overnight observation ward or may need ICU.